Article fMRI Study of Maintenance and Manipulation Processes Within Working Memory in First-Episode Schizophrenia Hao-Yang Tan, M.B.B.S., M.Med. Objective: Working memory, a critical tasks, patients showed less bilateral dor- cognitive capacity that is affected in solateral prefrontal cortex activation and Wei-Chieh Choo, M.B.B.S. schizophrenia, can be divided into main- greater ventrolateral prefrontal cortex ac- tenance and manipulation processes. Pre- tivation, relative to the comparison sub- vious behavioral research suggested that jects. A group-by-task interaction was ob- Calvin S.L. Fones, M.B.B.S., manipulation is more affected than main- served for activation at the left M.Med. tenance in patients with chronic schizo- dorsolateral and ventrolateral prefrontal phrenia. In this study of first-episode cortex. The increase in activation when Michael W.L. Chee, M.B.B.S., schizophrenia patients, the authors eval- patients engaged in the manipulation M.R.C.P. uated the extent to which the two work- plus maintenance task was disproportion- ing memory processes are affected early ately less in the dorsolateral prefrontal in the course of schizophrenia. cortex and greater in the ventrolateral Method: Study subjects were 11 first- prefrontal cortex. episode schizophrenia patients and 11 Conclusions: These functional neuroan- matched healthy comparison subjects. atomical findings add support to earlier Each group performed two verbal work- suggestions that manipulation of infor- ing memory tasks while undergoing func- mation is selectively more affected than tional magnetic resonance imaging. One maintenance of information in persons task required maintenance of informa- with schizophrenia. They also suggest the tion; the other required manipulation of presence of interacting regions of dys- information in addition to maintenance. functional and compensatory prefrontal Results: Under behaviorally matched responses in the dorsolateral and ventro- conditions, both groups activated a pre- lateral prefrontal cortex, respectively, that dominantly left-sided frontal-parietal net- are more prominent when information is work. The manipulation plus mainte- manipulated. This disrupted prefrontal nance task elicited activation of greater network is present relatively early in the magnitude and spatial extent. With both course of schizophrenia. (Am J Psychiatry 2005; 162:1849–1858) Working memory is a limited-capacity system that ating working memory engaged the various components enables maintenance and manipulation of information of this faculty but did not explicitly attempt to dissociate temporarily. It plays an important role in higher-order the effects of the illness on these components. An impor- thinking, language, and goal-directed behavior (1), and it tant goal of the present study was to explore this possibil- is an important facet of the cognitive dysfunction in schizo- ity in terms of the effect on prefrontal activation of the in- phrenia (2, 3). A number of neuroimaging studies have teraction of task component and disease. Illness-related sought to uncover the neural basis of working memory factors such as duration of illness, occupational and social deficits in patients with schizophrenia. Reduced dorsolat- deprivation, and substance abuse are thought to affect eral prefrontal cortex (i.e., Brodmann’s area 46, 9) activa- brain anatomy and function (12) and may be a further tion (4, 5), increased activation (6), an absence of differ- confounder in the effort to define disease-specific working ences in activation (7), and a combination of increased memory dysfunction. Thus, only first-episode schizophre- and decreased activation (8) have all been described. The nia patients were evaluated in our study. anatomically and functionally related ventrolateral pre- One approach that has pointed to specific dorsolateral frontal cortex (Brodmann’s area 44, 45, 47) has been re- prefrontal cortex dysfunction is isolation of context pro- ported to show decreased activation in some studies (9) cessing in working memory (4). Another approach, the but not in others (4, 8). one we used in this study, is to consider the maintenance These divergent findings could arise from non-disease- and manipulation processes separately. For a given load, related factors, for example, task performance (6, 10), the addition of explicit manipulation requirements results working memory load (6, 8), and the cognitive paradigm in increased activation, particularly in the dorsolateral used in the study (11). Many previous experiments evalu- prefrontal cortex, in normal individuals (13, 14). (Here, the Am J Psychiatry 162:10, October 2005 http://ajp.psychiatryonline.org 1849 WORKING MEMORY IN SCHIZOPHRENIA FIGURE 1. Sequence and Timing of the Maintenance of Letters and Manipulation Plus Maintenance of Letters Tasksa KM Maintenance + of Letters DC + Task 0.5 c second 3.0 + seconds 1.5 Manipulation seconds 0.5 Plus second Maintenance B + J 33 33 33 of Letters + seconds seconds seconds Task 0.5 c + Task Task Task second 3.0 33 33 33 33 seconds 1.5 seconds seconds seconds seconds seconds Control CC 0.5 second Control Control Control Control Condition + CC + 0.5 c second 0.3 + second 1.5 seconds 3.2 seconds a Adapted with permission from Chee and Choo (19). Copyright 2004 by the Society for Neuroscience. term “load” refers to the number of items that have to be subjects matched with the patients for gender, age, and educa- maintained in working memory [e.g., in a Sternberg-type tional level were recruited from the surrounding community of maintenance task]. “Task complexity” refers to the num- staff and students. All subjects were right-handed, as assessed by the handedness inventory (21). After a complete description of ber of cognitive processes required to perform a task. the study to the subjects, written informed consent was obtained “Task difficulty” is dependent on one or both of these con- in accordance with the National University Hospital and Sin- ditions; when comparing tasks tapping different domains, gapore General Hospital institutional review boards. as in the current study, reaction time and accuracy are All healthy comparison subjects were screened by a research used to gauge difficulty.) The dorsolateral prefrontal cor- physician (W.C.C.) with a standardized questionnaire to exclude tex also has a role in the maintenance of information (15, those with a past history of psychiatric, neurological, or serious medical disorders; IQ below 70; and drug or alcohol abuse in the 16), whereas the left ventrolateral prefrontal cortex and last 6 months. First-episode psychosis patients, who met similar left inferior parietal lobule are thought to participate in re- criteria, underwent functional magnetic resonance imaging hearsal processes that briefly maintain verbal information (fMRI) when they were clinically stabilized, as defined by a score (17, 18). of ≤3 on the Clinical Global Impression scale (22). At the time of scanning, all patients had been taking atypical antipsychotic In this study, we used two working memory tasks that medications for at least 1 month. None received anticholinergic evaluated prefrontal function associated with mainte- medications. Patients were followed up for at least 6 months after nance alone and with manipulation in addition to mainte- recruitment into the study. The diagnosis of schizophrenia was nance (19). We tested working memory using a two-by- made according to DSM-IV criteria and was corroborated by a di- two experimental design, with the expectation that pre- agnostic conference that included review of information from the Structured Clinical Interview for DSM-IV (23) that had been ad- frontal activation in the dorsolateral prefrontal cortex and ministered by a research psychiatrist (H.Y.T.) and from all avail- ventrolateral prefrontal cortex would diverge more promi- able medical records. In addition, the research psychiatrist ad- nently in patients, relative to comparison subjects, partic- ministered the Positive and Negative Syndrome Scale (24) and the ularly in the manipulation plus maintenance task, as sug- Global Assessment of Functioning Scale (DSM-IV, p. 32) to assess gested by recent behavioral experiments (20). symptom severity within a week before the fMRI scan. After 6 months of follow-up, three patients were excluded because they met the DSM-IV criteria for other diagnoses (two for schizoaffec- Method tive disorder and one for brief psychotic disorder). Two patients and two comparison subjects were excluded because of motion Patients and Comparison Subjects artifacts. To include patients early in the course of the illness, we re- Working Memory Tasks cruited first-episode psychosis patients and confirmed the diag- nosis of schizophrenia at 6-month follow-up. Originally, 16 pa- Two working memory tasks were used (Figure 1). The mainte- tients were recruited from among inpatients and outpatients nance of letters task evaluated maintenance of information and treated in a psychiatric unit of a teaching hospital, which was also was adapted from previous work (19, 25). Briefly, four different a setting for evaluation of community referrals from primary care uppercase letters were presented for 0.5 second, followed by a de- providers throughout Singapore. Thirteen healthy comparison lay of 3.0 seconds during which a fixation cross was displayed. A 1850 http://ajp.psychiatryonline.org Am J Psychiatry 162:10, October 2005 TAN, CHOO, FONES, ET AL. TABLE 1. Characteristics and Behavioral Performance on Working